Is C1S p.Gly243Arg (c.727G>A) pathogenic?

C1S p.Gly243Arg (c.727G>A) is classified Uncertain significance in C1S (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-11). AlphaMissense: likely benign (0.0909); Very rare (popmax 0.00102%, nfe); Associated with Ehlers-Danlos syndrome, periodontal type 2.

What condition is associated with C1S p.Gly243Arg (c.727G>A)?

C1S p.Gly243Arg (c.727G>A) is associated with Ehlers-Danlos syndrome, periodontal type 2 (ClinVar).

How common is C1S p.Gly243Arg (c.727G>A) in the general population?

C1S p.Gly243Arg (c.727G>A) is very rare (popmax 0.00102%, nfe) (gnomAD).

How is Periodontal Ehlers-Danlos syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about C1S p.Gly243Arg (c.727G>A)?

AlphaMissense predicts likely benign (score 0.0909) — an in-silico prediction, not a clinical call.

C1S p.Gly243Arg

c.727G>A · rs1388331401 · VCV2439618

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ehlers-Danlos syndrome, periodontal type 2

Computational evidence

Protein change
AlphaMissense	0.0909	likely benign
REVEL	0.22	benign-leaning
SaProt	LLR -9.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.49	acceptor loss, 9 bp away · masked 0 · deltas
Pangolin	Δ0.57	loss · gain 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.076	GERP -3.7
Regional constraint	o/e 0.98	unconstrained · MANE · 4,638 bp · p 0.66 · regional, not allelic
Overall
CADD	2.33	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00102% European (non-Finnish) · 12/1,179,802 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000744% 12/1,612,454 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: C1S
Protein: p.Gly243Arg
Coding: c.727G>A
MANE Select: NM_001734
dbSNP: rs1388331401
Type: single nucleotide variant
Location: chr12:7065826 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 243: a disulfide bond; the cub 2 domain

Full C1S gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Ehlers-Danlos syndrome, periodontal type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Periodontal Ehlers-Danlos syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

C1S p.Arg523Ter Pathogenic ★★ same condition
C1S p.Arg331Cys Uncertain significance ★★ ⚠ same condition
C1S p.Arg534Trp Uncertain significance ★★ ⚠ same condition
C1S p.Arg572Gln Uncertain significance ★★ ⚠ same condition
C1S p.Asn116Ser Uncertain significance ★★ ⚠ same condition
C1S p.Gly172Arg Uncertain significance ★★ ⚠ same condition
C1S p.Lys669Asn Uncertain significance ★★ ⚠ same condition
C1S p.Ser339Leu Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/c1s-p-gly243arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown